Chaperone mediated autophagy degrades TDP-43 protein and is affected by TDP-43 aggregation
Open accessAbstract
TDP-43 is a ribonuclear protein regulating many aspects of RNA metabolism. Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD) are fatal neurodegenerative diseases with the presence of TDP-43 aggregates in neuronal cells. Chaperone Mediated Autophagy (CMA) is a lysosomal degradation pathway participating in the proteostasis of several cytosolic proteins including neurodegenerative associated proteins. In addition, protein oligomers or aggregates can affect the status of CMA. In this work, we studied the relationship between CMA and the physiological and pathological forms of TDP-43. First, we found that recombinant TDP-43 was specifically degraded by rat liver’s CMA+ lysosomes and that endogenous TDP-43 is localized in rat brain’s CMA+ lysosomes, indicating that TDP-43 can be a CMA substrate in vivo. Next, by using a previously reported TDP-43 aggregation model, we have shown that wild-type and an aggregate-prone form of TDP-43 are detected in CMA+ isolated lysosomes isolated from cell cultures. In addition, their protein levels increased in cells displaying CMA down-regulation, indicating that these two TDP-43 forms are CMA substrates in vitro. Finally, we observed that the aggregate-prone form of TDP-43 is able to interact with HSC70 and Lamp2A, as well as to up-regulate the levels of these molecular components of CMA. The latter was followed by an up-regulation of the CMA activity and lysosomal damage. Altogether our data shows that, i) TDP-43 is a CMA substrate, ii) CMA can contribute to control the physiological and pathological forms of TDP-43 and iii) TDP-43 aggregation can affect CMA performance. Overall, this work contributes to understanding how a dysregulation between CMA and TDP-43 would participate in neuropathological mechanisms associated with TDP-43 aggregation. Keywords: TARDBP, protein aggregation, cellular model, Chaperone Mediated Autophagy, lysosomal damage, Amyotrophic Lateral Sclerosis
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Mutations in cathepsins D and F lead to NCL.
“Mutations in several of the cathepsins lead to NCL (D and F), and others have also been identified as risk factors for neurodegenerative disease (B, D, and F).88,122,123”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [123]
The Discussion (page unavailable) concerns TDP-43 aggregation and chaperone-mediated autophagy, not mutations in cathepsins D or F. Searches for cathepsin D and F mutations, NCL, and neuronal ceroid lipofuscinosis found no passage in our copy addressing the claim. (LLM, conf=0.77)
Experimental — accuracy not yet measuredCathepsins B, D, and F are risk factors for neurodegenerative disease.
“Mutations in several of the cathepsins lead to NCL (D and F), and others have also been identified as risk factors for neurodegenerative disease (B, D, and F).88,122,123”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [123]
The Introduction and Discussion discuss autophagy, TDP-43, and neurodegeneration, but do not identify cathepsins B, D, or F as disease risk factors. Searches for those cathepsins and for NCL mutations found only a reference to unspecified cathepsin-dependent activity, not the attributed claim. Page numbers are unavailable in our copy. (LLM, conf=0.76)
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- Authors
- Ormeño, F., Hormazabal, J., Moreno, J., Riquelme, F., Rios, J., Criollo, A., Albornoz, A., Alfaro, I. E., & Budini, M.
- Affiliations
- University of Chile (CL)
- Fundación Ciencia and Vida (CL)
- Clínica Alemana (CL)
- Corresponding author
- Budini, Mauricio
- ORCID
- Venue
- Frontiers in Molecular Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2020-02-18
- Volume
- 13
- Pages
- 19-19
- ISSN
- 1662-5099 (ISSN-L)
- PMC
- PMC7040037
- OpenAlex
- W3006458381
- Cited by
- 80
- References
- 65
- Citations by year
- 2026: 15 · 2025: 17 · 2024: 10 · 2023: 7 · 2022: 10 · 2021: 16 · 2020: 5
- FWCI
- 4.11
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Molecular Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Universidad de Chile (submittedVersion, cc-by-nc-nd)
- Funders
- Fondo Nacional de Desarrollo Científico y Tecnológico
- International Centre for Genetic Engineering and Biotechnology
- Fondo Nacional de Desarrollo Científico y Tecnológico y de Innovación Tecnológica
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- TDP-43, chaperone-mediated autophagy, protein aggregation, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, Hsc70, LAMP2A, lysosomal degradation, neurodegeneration, protein quality control, TARDBP
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